Disease modifying therapies for Parkinson's disease (PD) remain a major unmet medical need despite numerous large-scale clinical trials. Among the reasons for these disappointing outcomes to date is the choice of proposed therapeutic targets that appear not to be critical for disease development or progression. But our current understanding about the molecular pathogenesis of PD has provided new therapeutic targets and the opportunity to develop disease-modifying therapies. Accumulating evidence from human genetics, cell biology and animal model studies suggest that ?-synuclein is a key protein in this disease as it misfolds, aggregates and forms fibrils that can propagate across neurons, explaining the progressive nature of the disease and the emergence of additional disturbing symptoms including dementia. A strong driver of its pathological aggregation is its concentration in the brain. Accordingly, reducing the expression of ?-synuclein has the potential to mitigate downstream cascades of pathologic events and slow down neurodegeneration. We propose to identify small molecules that downregulate the expression of ?-synuclein using a novel approach that we have developed. Our lead identification strategy, named Inforna, is designed to target RNA and impart biological activity. In this project, we will use Inforna to design small molecules that inhibit ?-synuclein production, followed by optimizing these molecules for further development.